Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials
详细信息 查看全文
- 作者：Stephan Duparc (1)
Isabelle Borghini-Fuhrer (1)
Carl J Craft (1) (2)
Sarah Arbe-Barnes (3)
Robert M Miller (3)
Chang-Sik Shin (4)
Lawrence Fleckenstein (5) - 关键词：Pyronaridine ; artesunate ; Artemether ; lumefantrine ; Mefloquine-?artesunate ; Malaria ; Plasmodium falciparum ; Plasmodium vivax ; Randomized clinical trial
- 刊名：Malaria Journal
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：12
- 期：1
- 全文大小：327KB
- 参考文献：1. World Health Organization: / World Malaria Report. 2011. http://www.who.int/malaria/world_malaria_report_2011/9789241564403_eng.pdf
2. Roll Back Malaria Partnership Secretariat: / World Malaria Day. 2010. / Africa Update http://www.rollbackmalaria.org/ProgressImpactSeries/docs/wmd2010report-en.pdf
3. Mueller I, Galinski MR, Baird JK, Carlton JM, Kochar DK, Alonso PL, del Portillo HA: Key gaps in the knowledge of Plasmodium vivax , a neglected human malaria parasite. / Lancet Infect Dis 2009, 9:555-66. CrossRef
4. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM: Vivax malaria: neglected and not benign. / Am J Trop Med Hyg 2007, 77:79-7.
5. Guerra CA, Snow RW, Hay SI: Mapping the global extent of malaria in 2005. / Trends Parasitol 2006, 22:353-58. CrossRef
6. Guerra CA, Howes RE, Patil AP, Gething PW, Van Boeckel TP, Temperley WH, Kabaria CW, Tatem AJ, Manh BH, Elyazar IR, Baird JK, Snow RW, Hay SI: The international limits and population at risk of Plasmodium vivax transmission in 2009. / PLoS Negl Trop Dis 2009, 4:e774. CrossRef
7. World Health Organization: / Guidelines for the treatment of malaria (second edition). http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf
8. Wongsrichanalai C, Wimonwattrawatee T, Sookto P, Laoboonchai A, Heppner DG, Kyle DE, Wernsdorfer WH: In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand. / Bull World Health Organ 1999, 77:392-98.
9. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM: Evidence of artemisinin-resistant malaria in western Cambodia. / N Engl J Med 2008, 359:2619-620. CrossRef
10. World Health Organization: / Containment of malaria multi-drug resistance on the Cambodia-Thailand border. [ / Report of an informal consultation, Phnom Penh] / 29-0 January 2007 http://www.who.int/malaria/publications/multi_drug_resistance_en.pdf / 29-0 January 2007
11. World Health Organization: / Global malaria control and elimination: report of a meeting on containment of artemisinin tolerance. http://whqlibdoc.who.int/publications/2008/9789241596817_eng.pdf
12. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ: Artemisinin resistance in Plasmodium falciparum malaria. / N Engl J Med 2009, 361:455-67. CrossRef
13. Song J, Socheat D, Tan B, Seila S, Xu Y, Ou F, Sokunthea S, Sophorn L, Zhou C, Deng C, Wang Q, Li G: Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area. / Malar J 2011, 10:231. CrossRef
14. Wongsrichanalai C, Meshnick SR: Declining artesunate-mefloquine efficacy against falciparum malaria on the Cambodia-Thailand border. / Emerg Infect Dis 2008, 14:716-19. CrossRef
15. Rueangweerayut R, Phyo A, Uthaisin C, Poravuth Y, Binh T, Tinto H, Pénali L, Valecha N, Tien N, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin C-S, Fleckenstein L: Pyronaridine-artesunate versus mefloquine plus artesunate for malaria. / NEJM 2012, 366:1298-309. CrossRef
16. Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, Ler Moo C, Al-Saai S, Dondorp AM, Lwin KM, Singhasivanon P, Day NP, White NJ, Anderson TJ, Nosten F: Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. / Lancet 2012, 379:1960-966. CrossRef
17. Douglas NM, Anstey NM, Angus BJ, Nosten F, Price RN: Artemisinin combination therapy for vivax malaria. / Lancet Infect Dis 2010, 10:405-16. CrossRef
18. Baird JK: Resistance to therapies for infection by Plasmodium vivax . / Clin Microbiol Rev 2009, 22:508-34. CrossRef
19. Mueller I, Widmer S, Michel D, Maraga S, McNamara DT, Kiniboro B, Sie A, Smith TA, Zimmerman PA: High sensitivity detection of Plasmodium species reveals positive correlations between infections of different species, shifts in age distribution and reduced local variation in Papua New Guinea. / Malar J 2009, 8:41. CrossRef
20. World Health Organization Regional Office for the Western Pacific: / Interregional workshop on the control of vivax malaria in East Asia (Shanghai, China, 17-0 November 2003). http://whqlibdoc.who.int/wpro/2004/RS_2003_GE_42(CHN).pdf
21. Croft SL, Duparc S, Arbe-Barnes SJ, Craft JC, Shin CS, Fleckenstein L, Borghini-Fuhrer I, Rim HJ: Review of pyronaridine anti-malarial properties and product characteristics. / Malar J 2012, 11:270. CrossRef
22. Kayentao K, Doumbo OK, Pénali LK, Offianan AT, Bhatt KM, Kimani J, Tshefu AK, Tambwe JKH, Ramharter M, Martinez de Salazar P, Tiono AB, Ouédraogo A, Bustos MDG, Quicho F, Borghini-Fuhrer I, Duparc s, Shin C-S, Fleckenstein L: Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial. / Malar J 2012, 11:364. CrossRef
23. Poravuth Y, Socheat D, Rueangweerayut R, Uthaisin C, Pyae Phyo A, Valecha N, Rao BH, Tjitra E, Purnama A, Borghini-Fuhrer I, Duparc S, Shin CS CS, Fleckenstein L: Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. / PLoS One 2011, 6:e14501. CrossRef
24. Ramharter M, Kurth F, Schreier AC, Nemeth J, Glasenapp I, Belard S, Schlie M, Kammer J, Koumba PK, Cisse B, Mordmuller B, Lell B, Issifou S, Oeuvray C, Fleckenstein L, Kremsner PG: Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. / J Infect Dis 2008, 198:911-19. CrossRef
25. Tshefu AK, Gaye O, Kayentao K, Thompson R, Bhatt KM, Sesay SS, Bustos DG, Tjitra E, Bedu-Addo G, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L: Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. / Lancet 2010, 375:1457-467. CrossRef
26. Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B: In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax . / Antimicrob Agents Chemother 2010, 54:5146-150. CrossRef
27. Okombo J, Kiara SM, Mwai L, Pole L, Ohuma E, Ochola LI, Nzila A: Baseline in vitro activities of the antimalarials pyronaridine and methylene blue against Plasmodium falciparum isolates from Kenya. / Antimicrob Agents Chemother 2012, 56:1105-107. CrossRef
28. Zhang CL, Zhou HN, Wang J, Liu H: [ In vitro sensitivity of Plasmodium falciparum isolates from China-Myanmar border region to chloroquine, piperaquine and pyronaridine]. / Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 2012, 30:41-4.
29. World Health Organization: / Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria (WHO/HTM/RBM/2003.50). http://whqlibdoc.who.int/hq/2003/WHO_HTM_RBM_2003.50.pdf
30. Felger I, Beck HP: Genotyping of Plasmodium falciparum. PCR-RFLP analysis. / Methods Mol Med 2002, 72:117-29.
31. Medicines for Malaria Venture, World Health Organization: / Methods and techniques for clinical trials on antimalarial drug efficacy: genotyping to identify parasite populations. http://whqlibdoc.who.int/publications/2008/9789241596305_eng.pdf
32. Price R, van Vugt M, Phaipun L, Luxemburger C, Simpson J, McGready R, ter Kuile F, Kham A, Chongsuphajaisiddhi T, White NJ, Nosten F: Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. / Am J Trop Med Hyg 1999, 60:547-55.
33. Ribeiro IR, Olliaro P: Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. / Med Trop (Mars) 1998, 58:50-3.
34. Ringwald P, Bickii J, Basco L: Randomised trial of pyronaridine versus chloroquine for acute uncomplicated falciparum malaria in Africa. / Lancet 1996, 347:24-8. CrossRef
35. Ringwald P, Bickii J, Basco LK: Efficacy of oral pyronaridine for the treatment of acute uncomplicated falciparum malaria in African children. / Clin Infect Dis 1998, 26:946-53. CrossRef
36. Agomo PU, Meremikwu MM, Watila IM, Omalu IJ, Odey FA, Oguche S, Ezeiru VI, Aina OO: Efficacy, safety and tolerability of artesunate-mefloquine in the treatment of uncomplicated Plasmodium falciparum malaria in four geographic zones of Nigeria. / Malar J 2008, 7:172. CrossRef
37. Bhatt KM, Samia BM, Bhatt SM, Wasunna KM: Efficacy and safety of an artesunate/mefloquine combination, (artequin) in the treatment of uncomplicated P. falciparum malaria in Kenya. / East Afr Med J 2006, 83:236-42.
38. Bouyou-Akotet MK, Ramharter M, Ngoungou EB, Mamfoumbi MM, Mihindou MP, Missinou MA, Kurth F, Belard S, Agnandji ST, Issifou S, Heidecker JL, Trapp S, Kremsner PG, Kombila M: Efficacy and safety of a new pediatric artesunate-mefloquine drug formulation for the treatment of uncomplicated falciparum malaria in Gabon. / Wien Klin Wochenschr 2010, 122:173-78. CrossRef
39. Frey SG, Chelo D, Kinkela MN, Djoukoue F, Tietche F, Hatz C, Weber P: Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety. / Malar J 2010, 9:291. CrossRef
40. Krudsood S, Looareesuwan S, Tangpukdee N, Wilairatana P, Phumratanaprapin W, Leowattana W, Chalermrut K, Ramanathan S, Navaratnam V, Olliaro P, Vaillant M, Kiechel JR, Taylor WR: New fixed-dose artesunate-mefloquine formulation against multidrug-resistant Plasmodium falciparum in adults: a comparative phase IIb safety and pharmacokinetic study with standard-dose nonfixed artesunate plus mefloquine. / Antimicrob Agents Chemother 2010, 54:3730-737. CrossRef
41. Massougbodji A, Kone M, Kinde-Gazard D, Same-Ekobo A, Cambon N, Mueller EA: A randomized, double-blind study on the efficacy and safety of a practical three-day regimen with artesunate and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. / Trans R Soc Trop Med Hyg 2002, 96:655-59. CrossRef
42. Mayxay M, Keomany S, Khanthavong M, Souvannasing P, Stepniewska K, Khomthilath T, Keola S, Pongvongsa T, Phompida S, Ubben D, Valecha N, White NJ, Newton PN: A phase III, randomized, non-inferiority trial to assess the efficacy and safety of dihydroartemisinin-piperaquine in comparison with artesunate-mefloquine in patients with uncomplicated Plasmodium falciparum malaria in southern Laos. / Am J Trop Med Hyg 2010, 83:1221-229. CrossRef
43. Abdulla S, Sagara I, Borrmann S, D’Alessandro U, Gonzalez R, Hamel M, Ogutu B, Martensson A, Lyimo J, Maiga H, Sasi P, Nahum A, Bassat Q, Juma E, Otieno L, Bjorkman A, Beck HP, Andriano K, Cousin M, Lefevre G, Ubben D, Premji Z: Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial. / Lancet 2008, 372:1819-827. CrossRef
44. Hatz C, Soto J, Nothdurft HD, Zoller T, Weitzel T, Loutan L, Bricaire F, Gay F, Burchard GD, Andriano K, Lefevre G, De Palacios PI, Genton B: Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in nonimmune populations: a safety, efficacy, and pharmacokinetic study. / Am J Trop Med Hyg 2008, 78:241-47.
45. Mueller EA, van Vugt M, Kirch W, Andriano K, Hunt P, de Palacios PI: Efficacy and safety of the six-dose regimen of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in adolescents and adults: a pooled analysis of individual patient data from randomized clinical trials. / Acta Trop 2006, 100:41-3. CrossRef
46. Sagara I, Rulisa S, Mbacham W, Adam I, Sissoko K, Maiga H, Traore OB, Dara N, Dicko YT, Dicko A, Djimde A, Jansen FH, Doumbo OK: Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial. / Malar J 2009, 8:63. CrossRef
47. Naing C, Aung K, Win DK, Wah MJ: Efficacy and safety of chloroquine for treatment in patients with uncomplicated Plasmodium vivax infections in endemic countries. / Trans R Soc Trop Med Hyg 2010, 104:695-05. CrossRef
48. Mengesha T, Makonnen E: Comparative efficacy and safety of chloroquine and alternative antimalarial drugs: a meta-analysis from six African countries. / East Afr Med J 1999, 76:314-19.
49. White NJ: Cardiotoxicity of antimalarial drugs. / Lancet Infect Dis 2007, 7:549-58. CrossRef
50. Karbwang J, Na-Bangchang K, Thanavibul A, Bunnag D, Chongsuphajaisiddhi T, Harinasuta T: Comparison of oral artesunate and quinine plus tetracycline in acute uncomplicated falciparum malaria. / Bull World Health Organ 1994, 72:233-38.
51. Karbwang J, Bangchang KN, Thanavibul A, Bunnag D, Chongsuphajaisiddhi T, Harinasuta T: Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria. / Lancet 1992, 340:1245-248. CrossRef
52. Sowunmi A, Oduola AM: Efficacy of artemether in severe falciparum malaria in African children. / Acta Trop 1996, 61:57-3. CrossRef
53. Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, Ekala MT, Bouchier C, Esterre P, Fandeur T, Mercereau-Puijalon O: Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. / Lancet 2005, 366:1960-963. CrossRef
54. Bousema T, Okell L, Shekalaghe S, Griffin JT, Omar S, Sawa P, Sutherland C, Sauerwein R, Ghani AC, Drakeley C: Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. / Malar J 2010, 9:136. CrossRef
55. Sowunmi A, Balogun T, Gbotosho GO, Happi CT, Adedeji AA, Bolaji OM, Fehintola FA, Folarin OA: Activities of artemether-lumefantrine and amodiaquine-sulfalene-pyrimethamine against sexual-stage parasites in falciparum malaria in children. / Chemotherapy 2008, 54:201-08. CrossRef
56. Agnandji ST, Kurth F, Belard S, Mombo-Ngoma G, Basra A, Fernandes JF, Soulanoudjingar SS, Adegnika AA, Ramharter M: Current status of the clinical development and implementation of paediatric artemisinin combination therapies in Sub-Saharan Africa. / Wien Klin Wochenschr 2011,123(1):7-. CrossRef
57. Kurth F, Belard S, Adegnika AA, Gaye O, Kremsner PG, Ramharter M: Do paediatric drug formulations of artemisinin combination therapies improve the treatment of children with malaria? A systematic review and meta-analysis. / Lancet Infect Dis 2010, 10:125-32. CrossRef - 作者单位：Stephan Duparc (1)
Isabelle Borghini-Fuhrer (1)
Carl J Craft (1) (2)
Sarah Arbe-Barnes (3)
Robert M Miller (3)
Chang-Sik Shin (4)
Lawrence Fleckenstein (5)
1. Medicines for Malaria Venture (MMV), International Center Cointrin, Route de Pré-Bois 20, PO Box 1826, CH-1215, Geneva 15, Switzerland
2. Libertyville, IL, USA
3. Aptiv Solutions, Stevenage BioScience Catalyst, SG1 2FX, Stevenage, UK
4. Shin Poong Pharmaceutical Co Ltd, Seoul, Republic of Korea
5. College of Pharmacy, University of Iowa (UoI), Iowa City, IA, USA
文摘
Background Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Methods Individual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P. vivax (one study) malaria. Efficacy against P. falciparum was evaluated across three Phase III clinical trials. Results The safety population included 2,815 patients randomized to PA, 1,254 to comparators: mefloquine-?artesunate (MQ-?AS), artemether-lumefantrine (AL), or chloroquine. All treatments were generally well tolerated. Adverse events occurred in 57.2% (1,611/2,815) of patients with PA versus 51.5% (646/1,254) for comparators, most commonly (PA; comparators): headache (10.6%; 9.9%), cough (5.9%; 5.6%) and anaemia (4.5%; 2.9%). Serious averse events were uncommon for all treatments (0-.7%). Transient increases in alanine aminotransferase and aspartate aminotransferase were observed with PA but did not lead to any clinical sequelae. For P. falciparum malaria, day-28 PCR-corrected adequate clinical and parasitological response with PA was 93.6% ([1,921/2,052] 95% CI 92.6, 94.7) in the intent-to-treat population and 98.5% ([1,852/1,880] 95% CI 98.0, 99.1) in the per-protocol population. Median parasite clearance time was 24.1?h with PA, 31.9?h with MQ-?AS, and 24.0?h with AL. Median fever clearance time was 15.5?h with PA, 15.8?h with MQ-?AS, and 14.0?h with AL. By day 42, P. falciparum gametocytes had declined to near zero for all treatments. Conclusions Pyronaridine-artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first-line therapy. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes. Trial registration Clinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931